The aim of this research is to determine, to near atomic resolution, the fibert structure that results from the self assembly of sickle hemoglobin molecules in their deoxygenated conformation. Our X-ray diffraction studies have shown that the protofilament of the fiber is a double strand of molecules and that antiparallel pairs of such protofilaments combine to form the fiber. The detailed architecture and mapping of all intermolecular interactions within the fiber will be established utilizing diffraction data as a basis for computer model building. Electron diffraction from fibers in a single erythrocyte will be obtained by the use of a high voltage electron microscope with an environmental chamber where deoxygenated sickled erythrocytes remain under near physiological conditions. Inasmuch as diffraction patterns can be obtained in several seconds, the fibers will resemble closely those found in circulating erythrocytes. Because regions as small as 1Mum2 can be examined, the probability of finding domains in which all the fibers are paralleld is significantly increased. The improvement in resolution attainable witht this method over that of X-ray diffraction could be phenomenal. Our previos investigations have shown that the transform of the fiber is strikingly similar to the combined transforms of two monoclinic crystalline forms, I and II. Because the fiber structure is directly related to the crystalline structures, we propose to determine the structure of form II to near atomic resolution, as has already been done for form I. Model building will utilize information provided by both structures. Because of constraints dictated by the physical, chemical and structural properties of the fibers, the number of models to be tested is limited. Comparisons of calculated transforms of models with observed fiber patterns, particularly those of higher resolution obtained by electron diffraction, should establish the correct fiber structure. The complete topography of surface interactions determined by these studies will greatly increase the possibility of developing stereospecific agents to prevent fiber formation and thus alleviate sickle cell disease.